Certain esters of amino alcohols



2,882,276 CERTAIN ESTERS F AMINO ALCOHOLS Carl D. Lunsford, Richmond, Va., assignor to A. H.

Robins Company, Inc., Richmond, Va., a corporation of Virginia N0 Drawing. Application April 16, 1957 Serial No. 653,069 6 Claims. (Cl. 260326.3)

The present invention relates to esters of amino alcohols and more particularly to esters of N-cycloalkyl-3-pyrrolidinols. The concept of the present invention is illustrative by the molecular configuration appearing in the following structural formula:

where R=cycloalkyl, such as cyclopentyl, cyclohexyl or cycloheptyl.

R =H, alkoxy, alkyl.

alternatively be written as l-methyl-3-benz'oyloxy pyrrol-V idine. This reference differs from the compounds of the present invention in that it lacks the critical cycloalkyl group attached to the N or 1 position to which potency and duration of action of local anesthetic effect is primarily attributed. For example, in comparison as to potency with procaine and Xylocaine, the Berichte l-methyl- 3-benzoyloxy-pyrrolidine derivative gave anesthetic potency ratios of 0.95 and 1.10 whereas a typical compound of the present invention the corresponding l-cyclohexyl- 3-benzoyloxy pyrrolidine gave increased potency ratio of 1.63 and 1.70. Hill et al. IACS 76 pages 3548-50 (1954) discusses generally the dibenzoates of 3, 4 dihydroxy pyrrolidines which differ from applicants compounds in being additionally substituted at the 4 position of the pyrrolidine ring. Furthermore, there is no specific mention of the N-cycloalkyl derivative in the ester series.

The compounds of the present invention are also related generally to that class of known local anesthetics which are esters of para amino benzoic acid and benzoic acid having a specific effect on the sensory nerves or their endings. Among such known compounds are procaine and piperocaine.

It has been the aspiration of workers in the art to strive for relatively long action as well as high activity coupled with low toxicity. Procaine and Xylocaine, while most widely used, are not completely satisfactory local anesthetics. Therefore, it is an object of the present invention to provide novel benzoate esters of N-cycloalkyl- 3-pyrrolidinols.

It is a further object of the present invention to provide novel benzoyloxy esters of N-cycloalkyl substituted- B-pyrrolidinols wherein the number of cyclic carbon atoms ranges from 5 to 7.

rates Patent ICC It is an additional object of the present invention to provide novel local anesthetic compositions having high activity and long duration compared to known com positions.

Other objects of the invention will become apparent to those skilled in the art to which this invention pertains.

Members of the new group of compounds include esters of 3-pyrrolidinols wherein the N- or 1- position is substituted by a cycloalkyl hydrocarbon radical such as cyclopentyl, cyclohexyl and cycloheptyl.

The esterification at the 3 position may be by a simple benzoyloxy or benzoic acid moiety or by a benzoyloxy fraction substituted by alkyl or alkoxy. The ultimate compounds are preferably used in the form of their soluble hydrohalide salts such as the hydrochloride.

Representative examples of the compounds included within the scope of the present invention are l-cyclopentyl-S-benzoyloxy pyrrolidine hydrochloride, l-cyclohexyl-3 benzoyloxy pyrrolidine hydrochloride, l-cyclohepty1-3-benzoyloxy pyrrolidine hydrochloride when the benzoyloxy moiety is unsubstituted. In the compounds where alkoxy is substituted in the benzoyloxy moiety, it is preferable that the substitution be in the para position. Representative examples showing 1-cycloalkyl-3-p-alkoxy substituted benzoyloxy pyrrolidines include: l-cyclohexyl- S-p-n-butoxybenzoyloxy pyrrolidine hydrochloride and 1- cyclohexyl-3-p-methoxybenzoyloxy pyrrolidine. In the compounds where alkyl is substituted in the benzoyloxy moiety, the alkyl substituent may be single or multiple. Representative examples of l-cycloalkyl-3 alkyl substituted benzoyloxy pyrrolidines include 1-cyclohexyl-3- o-methylbenzoyloxy pyrrolidine and (2,4,6-trimethylbenzoyloxy) pyrrolidine hydrochloride.

The novel compounds of the present invention are prepared by the reaction of the appropriate N-cycloalkyl-3- pyrrolidinol with a benzoic acid halide such as benzoyl chloride, or a substituted benzoyl chloride.

Since many of the starting N-substituted-3-pyrrolidinols are themselves novel compounds, generalized methods for their preparation are given in detail in the following preparations and examples: The 1-cyc1oalkyl-3 pyrrolidinols are prepared in the same manner as the 1-alkyl-3 pyrrolidinols shown in the examples.

PREPARATION OF 3-PYRROLIDINOLS (a) The 1-substituted-3pyrrolidinol amino alcohol starting materials may be conveniently prepared by a ring formation process using the corresponding dihalo mono hydroxy alkane and a primary amine similar to the method disclosed at 76 J.A.C.S. 3548 (1954):

1-n-BUTYL-3-PYRROLIDINOL Into a 3 liter, round bottom, three neck flask fitted with a mechanical stirrer, condenser, dropping funnel and thermometer was introduced 731 grams (approximately 10 moles) of n-butylamine, and it was heated to reflux. The heating source was removed and 1155 grams (approximately 5 moles) of 1,4-dibromo-2-butanol was added dropwise, with stirring, at a rate which maintained refluxing of the amine. When the temperature of the mixture became -140 C. it was maintained there by adjusting the rate of addition of the 1,4-dibromo-2- butanol and for an additional two hours by external heating after addition was complete. Approximately one liter of water was added to the reaction mixture, and the resulting solution was acidified with concentrated hydrochloric acid, cooled and extracted with ether. The aqueous layer was basified with 50 percent aqueous sodium hydroxide, saturated with potassium carbonate and extracted with chloroform. The chloroform solution was concentrated and the residue was fractionally distilled at reduced pres- 3 sure; yield 440 grams (62 percent); 113.1. 120-124 C. atZZmThl Analysis.Calculated for C H NOz C, 67.09 percent; H, 11.96' percent. Found: C, 6709 percent; H, 12.11 percent.

The' l,4'-dibrorno-2-butanol used in the preparation of the l-substituted-3 pyrrolidinols is conveniently prepared according to the following procedure:

1,2,4-butanetril (2120 grams, 20 moles) was heated in a three liter, round bottom, three neck flask fitted with a gas inlet tube, thermometer and water separator to 120 C. A rapid stream of dry hydrogen bromide was passed in and the temperature was maintained at 130-140 C. for approximately two hoursuntil approximately 90 percent of the stoichiometric amount of water had separated. The remaining water was removed in vacuo and the residue distilled at reduced pressure; yield 3490 grams (75 percent); boiling range 153l60 C. at 45 mm. (98 C. at 3.5 mm.)

(b) The l-substituted 3 pyrrolidinol starting materials may also be prepared by reduction of the corresponding ketones with suitable reducing agents. The ketones per se are well-known in the art, e.g., 73 J.A.C.S. 2372 (1951) and are generally prepared by the Dieckmann Cy'clization Reaction.

1-BUTYL-3-PYRROLIDINOL To illustrate this latter process wherein lithium aluminum hydride is employed for reduction, 1-butyl-3-pyrroli-done (16.0 g.-, 0.113 mole) was added dropwise with stirring to a suspension of 3.0 grams (0.077 mole) of lithium aluminum'hydride in 300 m1. of dry ether. The mixture was refluxed and stirred for 30 minutes after all ketone was added. The excess hydride was hydrolyzed with water and the mixture filtered. The ether filtrate was concentrated and distilled through a 6" Vigreux column. The l-butyl-3-pyrrolidinol was collected at 138 -139f" C. at 37 mm. pressure. Yield 13.0 g'., 0.91- mole (80.5 percent).

1-ETHYL-3-PYRROLIDINOL To illustrate the use of sodium. borohydride as the reducing agent for the preparation of the 3-pyrrolidinols, the 1-ethyl-3-pyrrolidone resulting from ring closure of 231 g. (1.0 mole) of fl-carbethoxyethyl-carbethoxymethylethylamine with sodium ethoxide followed by acid hydrolysis and decarboxylation of the N-ethyl-pyrrolidone ester was treated with a slight excess. of sodium borohydride (0.28 mole) in aqueous solution near neutrality and allowed to stand at room temperature overnight. The complex was hydrolyzed with excess 50 percent sodium hydroxide and the pyrrolidinol was extracted into chloroform. The chloroform extract was concentrated and the 1-ethyl-3-pyrrolidinol was fractionated to give 27 grams (0.235 mole, 23.5 percent) of clear white oil boiling at 117-118 C. at 39 mm.

The following examples illustrate the preparation of the compounds of the present invention:

Example 1.1-cycI0hexyl-3-benzoyl0xy pyrrolidine hydrochloride To a stirred solution of 152 grams (0.9 mole) of 1- cyclohexyl-3-pyrrolidinol in 500 ml. of dry benzene there was added 126 grams (0.9 mole) of benzoyl chloride dropwise while the temperature was maintained at 20 to 25 C. by cooling with an ice bath. After complete addition the solution was warmed to reflux and reflux was continued for two hours. The mixture was then cooled and precipitation was initiated by addition of a little ligroin. The solid was filtered with suction and recrystallized from a mixture of butanone and methanol, or ethyl acetate and ethanol; or from toluene. Yield 272 grams (88 percent) of 3-benzoyloxy pyrrolidine hy-' drochloride; M.'P. 157-1-59" C. In appearance'this compound was" a white crystalline solid which was soluble in water, alcohol and propylene glycol. weight was 309.83.

The molecular Analysis:

Calculated for C H O NHCI 11.44 percent Cl. Found 11.26 percent CI.

l-cyclopentyl-3-benzoyloxy pyrrolidine hydrochloride and l-cycloheptyl-3-benzoyloxypyrrolidine hydrochloride were prepared in an analogous manner. These compounds, characteristic of the series, were also white powders which were water soluble. Additional identifying fingerprint data is set out in Table 1.

Example 2 .-1 -cycl0hexyl-3 (2,4,6 -trimethy lbenzoyloxy) pyrrolidine hydrochloride Example 3.1-cyclohexyl-3-(p-n-butoxybenzoyloxy) pyrrolidine hydrochloride To a solution of 16.9 grams (0.10 mole) of 1-cyclohexyl-3-pyrrolidinol in about ml. of benzene there was added in several portions 21.3 grams (0.10 mole) of p-n-butoxybenzoyl chloride, and the mixture was refluxed: for two hours and cooled. The product was precipitated.

by addition of dry ether and crystallized from ethyl acetate; Yield 21 grams (55 percent) of 1-cyclohexyl-3- (p-n-butoxybenzoyloxy) pyrrolidine hydrochloride; M.P. 148-449 C. The product was a white powder soluble inv water and hot ethyl acetate. The molecular weight (m.w.) was 382.94.

Ina manner similar to the specific examples set out in Examples 1-3, additional compounds were prepared", and identifying fingerprint data for such compounds.

is presented in Table I. Duration of local anestheticactivity, in relationship to procaine and Xylocaine is also set forth.

PHARMACOLOGY EXPERIMENTS A The compounds of the present invention were tested in' vivo in rabbits for duration of local anesthetic action according to the following method (Spinal Anesthesia Duration of Action).

Albino rabbits of either sex were used in the studies. All tested compounds were prepared in 1.0 percent solutions in physiological saline and injected intraspinally' according to the method of Bieter et al., J. Pharmacol. and Exp. Therap. 57, 221 (1936). Xylocaine hydrochloride was used as a positive control. Each rabbit received a volume of 0.02 ml. of one of the solutions per centimeter of spinal length.

Motor paralysis was determined by observing abnormalities in positioning which occurred in both hind extremities. Sensory paralysis was determined by pricking the trunk and limbs of the animals with a needle. Duration' of anesthesia represents the time interval between onset of anesthesia and the return of sensory perception and normal motor function of the hind limbs. Observations were made approximately every five minutes.

Since all materials were screened at a concentration of 1.0 percent, evaluation of efiectiveness is based on duration of anesthesia.

' Cephalic penetration through the spinal cord was establislied by testing the sensory paralysis on each side of the vertebral column throughout its length. All compounds showed penetration up the cord which was suflicient to abolish sensation over most of the abdominal surface. 1-cyclohexy1-3-(2,4,6 trimethylbenzoyloxy) pyrrolidine hydrochloride and 1-cyclohexyl-3-(p-n-butoxybenzoyloxy) pyrrolidine hydrochloride apparently penetrated up through the thoracic area, since sensation was abolished over the thorax and front,limbs in some rabbits. No embarrassment to respiration was apparent.

1-cyclohexyl-3-(2,4,6-trimethylbenzoyloxy) pyrrolidine hydrochloride and 1-cyclohexyl-3-(p-n-butoxybenzoyloxy) pyrrolidine hydrochloride were found to be most potent materials of this group as evidenced by their prolonged duration of action. 1-cyclohexyl-3-(o-methylbenzoyloxy) pyrrolidine hydrochloride, l-cyclohexyl 3 (p methoxybenzoyloxy) pyrrolidine hydrochloride and l cyclopentyl- 3-benzoyloxy pyrrolidine hydrochloride appear to act from one to two times as long as Xylocaine.

It would appear from the basis of structure that the substituted benzoic acid esters in the l-cyclohexyl series where the substituent was lower alkyl or 'alkoxy gave peak activity, as with 1-cyclohexyl-3-(2,4,6-trimethylbenzoyloxy) pyrrolidine hydrochloride and l-cyclohexyl- 3-(p-n-butoxybenzoyloxy) pyrrolidine hydrochloride. The least active compound as to duration of activity appeared to be the C or l-cycloheptyl-3 benzoyloxy pyrrolidine hydrochloride which gave values roughly equivalent to the procaine used as a standard.

The remainder of the compounds gave unexpectedly long duration of activity as to both motor paralysis and sensory paralysis ranging upward to six times the duration as compared with Xylocaine and twelve times the activity as compared with procaine with the compounds of peak activity. Furthermore, referring to Table 1, comparison data indicates that the p-methoxy compound where the 1 position is cyclohexyl is several times as active as the corresponding p-methoxy compound where the 1 or N position is alkyl such as isobutyl or ethyl indicating graphically the influence of the cycloalkyl radical in the N or 1 position in the pyrrolidine ring.

PHARMACOLOGY EXPERIMENTS B Additional pharmacological evaluation was made as to potency in comparing 1-cyc1ohexyl-3-benzoyloxy pyrrolidine hydrochloride with a known compound again using Xylocaine and procaine as base controls. The method used was by in vivo experiments in guinea pigs as follows:

The backs of white guinea pigs were close clipped and the test material were injected intradermally into the clipped skin area. 1 Four pigs were used per dilution 'of candidate material, procaine and Xylocaine were prepared. Xylocaine (base) was solubilized in physiological saline by the addition of one equivalent of hydrochloric acid. The volume of 0.25 ml. of the respective dilution of each compound and ofphysiological saline was injected intradermally in parallel rows on each side of the mid-line, and the resulting wheals were marked forfuture identification. In order to neutralize any difference in sensitiveness between frontal and caudal areas, the injection sites for any one dilution of the materials were alternated among the four pigs.

The wheals were tested five minutes after injection and every five minutes thereafter for thirty minutes. At each test, the wheals were stimulated by a series of six pin pricks. Number of pricks which failed to evoke a reflex skin twitch or phonation were counted for each test. The maximal test score for complete anesthesia, which continued for 30 minutes, would be 36. The comparison of potency of the compounds depended upon plotting the logarithm of the dilution against the average number of anesthetic responses (30 minute period) in each group of guinea pigs. A total of five anesthetic responses was considered the threshold anesthetic dose (TAD and furnished the basis for comparison. The TAD was read from the graph and then expressed as a ratio to the controls, Xylocaine and procaine.

These data demonstrated that 1-cyclohexyl-3-benzoyloxy pyrrolidine hydrochloride possesses local anesthetic action. According to the TAD 1-cyclohexyl-3 benzoyloxy pyrrolidine hydrochloride is 1.63 times more effective than Xylocaine and 1.70 times more effective than procame.

In a similar manner, the compound 1-methyl-3 benzoyloxy pyrrolidine hydrochloride, referred to in 22 CA 1774 (1928) was tested. According to the TAD this compound was only 0.95 as effective as Xylocaine and only 1.10 more effective than procaine.

Thus by comparison the effect of cyclohexyl as opposed to the known methyl compound at the 1 position was reflected in an increase of activity of about percent.

This application is a continuation-in-part application of my earlier filed application Serial No. 585,403, Lunsford, filed May 17, 1956, now US. Patent No. 2,838,521 entitled Esters of Amino Alcohols.

TABLE I.l-CYCLOALKYL-3-BENZOYLOXY PYRROLIDINES R CE: JH:

/N+\ Cl" H R h Av. duratifin 051 Molecular Wei t spina anes es g Yield Melting in rabbits Solu- R R Per- Point Calculated for 01 Found bilityg cent) C.) Hydro- Motor Sensory Base chloride Paralysis, Paralysis,

Min. Min.

295. 81 1 H Cy-CsHa 38 123-124 C1aH2iNO2.HCl 11. 98 11. 86 25 19 309. 83 1, 4, 5 H CyCaH1r 88 157-159 C17H2aNOr HCl 11. 44 11.26 23 21 323.86 1 H (Dy-07H 86 155-156 CraHzaNOz HCl 10. 95 10.93 10 9 823. 86 1 O-CHa Cy-CuHu 145-147 CrsHrsNO: H01 10.95 10.98 40 31 316. 45 352. 92 1, 3 2, 4, 6-(CH2): Oy-CsHu 34 183-185 O2uH29NOz.HC1 10.05 9. 87 120 304. 39 340.86 1, 2, 3 p-CHaO Cy-CuHn 154-156 O1aH2sNO2.HCl 10. 43 10. 45 41 15 346. 47 382. 94 1. 2 p-n-O4HsO Cy-OaH 55 148-149 Cz1H3 NO3.HCI 9. 28 9. 37 114 102 Xylocaine 18 17 procaine /CH: 9 9

278. 36 314. 83 1, 3 p-OHaO -0 H2011 63 127-129 GioHnNOa.HOl 11. 30 11. 59 7 10 285. 77 1 p-CHzO -C:Hu 43 123-124 G14HmNOa.HC1 12. 41 12. 53 12 12 Solubility-Soluble in: 1. Water; 2. Hot ethyl acetate; 3. Isopropanol;

4. Alcohol; 5. Propylene glycol.

Various; modificationsmay be made in the compositions of the present invention. and 'it: is to be understood. that the invention is: to be. limited only by the scope of" the appended claims.

I. claim:

1. 1;-cyclohexyl.-3-(2,4,6etrimethylbenzoyloxy) pyrrolidine hydrochloride.

2. 1-cyclohexyl-3-(p-n-butoxybenzoyloxy) pyrrolidine hydrochloride.

3. 1-cyclohexyl-3-(o-methylbenzoyloxy) pyrrolidine hydrochloride'.

4. 1-cyclohexyl-3-(p-methoxybenzoyloxy) pyrrolidine hydrochloride.

5. 1-cyclopentyl-3-benzoyloxy pyrrolidinehydrochloride.

6. A compound selected from the group consisting of 11-cycloalkyl-3-benzoyloxy pyrrolidines and pharmaceutically acceptable acid addition salts thereof wherein the cycloalkyl substituent is selected from the group consisting of cyclopentyl, cycl'ohexyl and Qycloheptyl and the benzoy-loxy substituent is elected from. the group con- Dickison et a1. Mar; 13, 1956- 2,838,521 Lunsford June 10, 1958 2,846,437- Elpem' Aug. 5-, 1958 FOREIGN PATENTS 946,708 Germany Aug. 2, 1956.

OTHER REFERENCES Mannich et aL: Berichte, 61 B pp. 263-268 (1938').

Ianssen et al.: Arch. Intern Pharmacodynarnie, vol. 103, pp. 89-91 (1955).

Elpern et 211.: J. Am. Chem. Society, vol. 79, pp. 1951-1952.

Perrine et al.: J; Org. Chem, vol. 21 (1956), pp.

Weijlard. et al.: J. Am- Chem. Society, vol. 78, pp. 2342-3. (.1956). 

6. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1-CYCLOALKYL-3-BENZOYLOXY PYRROLIDINES AN PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF WHEREIN CYCLOALKYL SUBSTITUENT IS SELECTED FROM THE GROUP CONSISTING OF CYCLOPENTYL, CYCLOHEXYL AND CYCLOHEPTYL AND THE BENZOYLOXY SUBSTITUENT IS SELECTED FROM THE GROUP CONSISTING OF UNSUBSTITUTED BENZOYLOXY, LOWER ALKYL BENZOYLOXY AND LOWER ALKOXY BENZOYLOXY. 